Reactions of substituted 8-oxatricyclo[3.2.1.02,4]octan-6-ones and 9-oxatricyclo[3.3.1.02,4]nonan-6-ones with methylmagnesium bromide and lithium aluminum hydride

Substituted 8-oxatricyclo[3.2.1.0^2,4]octan-6-one and 9-oxatricyclo[3.3.1.0^2,4]-nonan-6-one obtained by treating substituted cyclopropenes with carbonyl ylides in reactions with methylmagnesium bromide and lithium aluminum hydride were stereoselectively converted into the corresponding alcohols.     

First Example of 1,3-Dipolar Cycloaddition of Carbonyl Ylides to Cyclopropenes

Carbonyl ylide generated from 1-diazo-5-phenylpentane-2,5-dione in the presence of Rh₂(OAc)₄ reacts with 3-substituted cyclopropenes following the 1,3-dipolar cycloaddition pattern to afford substituted 9-oxatricyclo[3.3.1.0^2,4]nonan-6-ones.     

Nitrone cycloadditions to 1,2-diphenylcyclopropenes and subsequent transformations of the isoxazolidine cycloadducts

1,3-Dipolar cycloaddition of C-aryl,N-aryl (or N-methyl) nitrones with a number of 1,2-diphenylcyclopropenes substituted at the C(3) position occurs with the formation of expected "normal" cycloadducts (with N-methylnitrones) and products of their subsequent transformations. Among them are corresponding alpha-acetophenyl aziridines and tetra (or penta) -arylpyrroles. Aziridines and the normal cycloadducts can be also thermally converted to such arylpyrroles with moderate to good yields. Substitution at the C(3( position of cyclopropenes by an electron acceptor group decreases the reactivity of cyclopropenes.     

Rhodium(II) mediated cyclizations of diazo alkynyl ketones

The rhodium(II)-catalyzed reaction of -diazo ketones bearing tethered alkyne units represents a new and useful method for the construction of a variety of substituted cyclopentenones. The process proceeds by addition of the rhodium-stabilized carbenoid onto the acetylenic π-bond to give a vinyl carbenoid intermediate. The resulting rhodium complex undergoes a wide assortment of reactions including cyclopropanation, 1,2-hydrogen migration, CH-insertion, addition to tethered alkynes and ylide formation. The exact pathway followed is dependent on the specific metal/ligand employed and is also influenced by the nature of the solvent. Sulfonium ylide formation occurred both intra and intermolecularly when the reaction was carried out in the presence of a sulfide. In the case where an ether oxygen was present on the backbone of the vinyl carbenoid, cyclization afforded an oxonium ylide which underwent a [1,2] or [2,3]-sigmatropic shift to give a rearranged product. These cyclic metallocarbenoids were also found to interact with a neighboring carbonyl π-bond to produce carbonyl ylide dipoles that could be trapped with added dipolarophiles. The domino transformation was also performed intramolecularly by attaching an alkene directly to the carbonyl group. When 2-alkynyl-2-diazo-3-oxobutanoates were treated with a Rh(II)-catalyst, furo[3,4-c]furans were formed in excellent yield. The 1,5-electrocyclization process involved in furan formation has also been utilized to produce indeno[1,2-c]furans. Rotamer population was found to play a significant role in the cyclization of -diazo amide systems containing tethered alkynes. In this account, an overview of our work in this area is presented.     

Synthesis and Chemistry of Bicyclo[4.1.0]hept-1,6-ene

Bicyclo[4.1.0]hept-1,6-ene has been generated by elimination of 1-chloro-2-(trimethysilyl)bicyclo[4.1.0]heptane in the gas phase over solid fluoride at 25 degrees C. The cyclopropene dimerizes by a rapid ene reaction forming two diastereomeric cyclopropenes. In tetrahydrofuran or chloroform the ene dimers couple to form a single crystalline triene tetramer, whereas a mixture of tricyclohexane tetramers is formed when the neat dimers are allowed to warm to room temperature. Oxidation by dimethyldioxirane or dioxygen gives carbonyl products. Quantum mechanical calculations yielded an increase in strain of approximately 17 kcal/mol over that for 1,2-dimethylcyclopropene. The potential enegy barrier to flexing (folding) along the fused double bond of bicyclo[4.1.0]hept-1,6-ene is only approximately 1 kcal/mol at the highest level of theory investigated.     

Rhodium(II)-catalyzed cyclization of amido diazo carbonyl compounds

A series of acyclic diazo ketoamides were prepared from N-benzoyl-N-alkylaminopropanoic acids and were treated with a catalytic amount of rhodium(II) acetate. The resultant carbenoids underwent facile cyclization onto the neighboring amide carbonyl oxygen atom to generate seven-membered carbonyl ylide dipoles. Subsequent collapse of the dipoles with charge dissipation produce bicyclic epoxides which undergo further reorganization to give substituted 5-hydroxydihydropyridones in good yield. Depending on the nature of the substituent groups, it was possible to trap some of the initially formed carbonyl ylide dipoles with a reactive dipolarophile such as DMAD. In other cases, cyclization of the dipole to the epoxide is much faster than bimolecular trapping. A related cyclization/rearrangement sequence occurred when diazo ketoamides derived from the cyclic pyrrolidone and piperidone ring systems were subjected to catalytic quantities of Rh(II) acetate. With these systems, exclusive O-cyclization of the amido group onto the carbenoid center occurs to generate a seven-ring carbonyl ylide dipole. Starting materials are easily prepared, and the cascade sequence proceeds in good yield and does not require special precautions. The overall procedure represents an efficient one-pot approach toward the synthesis of various indolizidine and quinolizidine ring systems.     

The Synthesis and Chemistry of 1,3‐Bridged Polycyclic Cyclopropenes: 8‐Oxatricyclo[3.2.1.02,4]octa‐2,6‐dienes

Three 1,3‐bridged polycyclic cyclopropenes, exo‐8‐oxatricyclo[3.2.1.0^2,4]octa‐2,6‐diene ( 10 ), endo‐8‐oxatricyclo[3.2.1.0^2,4]octa‐2,6‐diene ( 11 ), and exo‐6,7‐benzo‐1,5‐diphenyl‐8‐oxatricyclo[3.2.1.0^2,4]octa‐2,6‐diene ( 12 ), have been synthesized by elimination of 2‐chloro‐3‐trimethylsilyl‐8‐oxatricyclo[3.2.1.0^2,4]‐oct‐6‐enes, 17 , 18 and 30 , which were generated from 1‐chloro‐3‐trimethylsilylcyclopropene with furan and diphenylisobenzofuran. We have demonstrated a facile route to synthesize the highly strained 1,3‐fused polycyclic cyclopropenes, 10 , 11 , and 12 . The stereochemistry of the Diels‐Alder reactions of cyclopropene 16 with furan and DPIBF are different. Cyclopropene 16 was treated with furan to form exo‐exo and endo‐exo adducts (5:2) and treated with DPIBF to generate an exo‐exo adduct. Compounds 10 , 11 and 12 undergo isomerization reactions to form benzaldehyde and phenyl 4‐phenyl‐[1]naphthyl ketone to release strain energies via diradical mechanisms.     

Fused vs. spiro: Kinetic,not thermodynamic preference may direct the reaction of α-carbonyl oxonium ylides

Rh(II)-catalyzed decomposition of certain cyclic α-diazocarbonyl compounds in the presence of cyclic ethers has been shown to give bicyclic ring expansion products. These are thought to arise from a [1,4]-alkyl shift toward the carbonyl oxygen atom and are in contrast with the recently observed spirocyclic products of a Stevens-type [1,2]-alkyl shift within the postulated oxonium ylide intermediate. Quantum chemical calculations performed at the B3LYP/6-31G* level of theory showed that the former reaction pathway (toward fused bicycles) is kinetically preferred.     

Dianion approach to chiral cyclopropene carboxylic acids

[reaction: see text] In this Letter, we describe a general method for preparing the dianions of cyclopropene carboxylic acids, and we show that their subsequent reactions with electrophiles provide a general means for selectively introducing diverse types of functional groups. This provides a general method for the synthesis of chiral 1,2-disubstituted cyclopropenes, and opens new avenues for the enantioselective preparation of cyclopropenes.     

Accurate prediction of rate constants of Diels-Alder reactions and application to design of Diels-Alder ligation

Bioorthogonal reactions are useful tools to gain insights into the structure, dynamics, and function of biomolecules in the field of chemical biology. Recently, the Diels-Alder reaction has become a promising and attractive procedure for ligation in bioorthogonal chemistry because of its higher rate and selectivity in water. However, a drawback of the previous Diels-Alder ligation is that the widely used maleimide moiety as a typical Michael acceptor can readily undergo Michael addition with nucleophiles in living systems. Thus, it is important to develop a nucleophile-tolerant Diels-Alder system in order to extend the scope of the application of Diels-Alder ligation. To solve this problem, we found that the theoretical protocol M06-2X/6-31+G(d)//B3LYP/6-31G(d) can accurately predict the activation free energies of Diels-Alder reactions with a precision of 1.4 kcal mol(-1) by benchmarking the calculations against the 72 available experimental data. Subsequently, the electronic effect and ring-strain effect on the Diels-Alder reaction were studied to guide the design of the new dienophiles. The criteria of the design is that the designed Diels-Alder reaction should have a lower barrier than the Michael addition, while at the same time it should show a similar (or even higher) reactivity as compared to the maleimide-involving Diels-Alder ligation. Among the designed dienophiles, three substituted cyclopropenes (i.e. 1,2-bis(trifluoromethyl)-, 1,2-bis(hydroxylmethyl)- and 1,2-bis(hydroxylmethyl)-3-carboxylcyclopropenes) meet our requirements. These substituted cyclopropene analogs could be synthesized and they are thermodynamically stable. As a result, we propose that 1,2-bis(trifluoromethyl)-, 1,2-bis(hydroxylmethyl)- and 1,2-bis(hydroxylmethyl)-3-carboxylcyclopropenes may be potential candidates for efficient and selective Diels-Alder ligation in living systems.     

Generation of functionalized azomethine ylides and their application to stereoselective heterocycle synthesis: an equivalent process of C-unsubstituted nitrile ylide cycloaddition reaction

The synthetic process equivalent to C-unsubstituted (CH) nitrile ylides cycloaddition reaction is achieved via cycloaddition of NH-azomethine ylide and the following fission reaction of the cycloadducts under acidic conditions. Cycloaddition of NH-azomethine ylide generated by a thermal 1,2-prototropy in 4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carbaldehyde system with maleimides provides proline derivatives under extremely mild conditions. Heating their adducts in AcOH at 85 °C causes a cleavage of C-C bond between the proline and heterocyclic moiety to give the parent heterocyclic system and dehydroproline derivatives, which is regarded as a cycloadduct of C-unsubstituted (CH) nitrile ylide. This cycloaddition-fission reaction sequences can be applied to one-pot three-component reaction.     

取代戊二烯Ti,V羰基化合物的谱学研究

利用IR，EPR和UV-VIS方法对系列取代戊二烯基钛，钒羰基化合物进行了表征，用EHMO方法对开环夹心化合物[2,4-(CH_3)_2C_2H_5]_2VCO和开、闭环夹心化合物[2,4(CH_3)_2C_5H_5](C_5H)5)VCO进行了计算，对开环夹心羰基化合物，开、闭环夹心羰基化合物及闭环夹心羰基化合物进行了比较．结果表明，开、闭环夹心羰基化合物的性质介于开环夹心羰基化合物和闭环夹心羰基化合物之间，且更接近于开环夹心羰基化合物，开环配体与Ti，V间的化学键较强，对于化合物性质影响较大．     

Intermolecular 1,5-dipolar cycloaddition reaction of tungsten-containing vinylazomethine ylides leading to seven-membered heterocycles

[STRUCTURE: SEE TEXT] Intermolecular 1,5-dipolar cycloaddition reaction of tungsten-containing vinylazomethine ylide, generated from o-(alk-3-en-1-ynyl)phenylbenzaldimines and tungsten carbonyl complex, with ketene acetals proceeds efficiently to give azepino[1,2-a]indole derivatives in good yield. Formation of [5+2] or [3+2] cycloadducts can be controlled by an appropriate choice of dipolarophile.     

Condensations of γ-Acetylacetonephosphonium Ylide (1-(Triphenylphosphoranylidene) pentane-2,4-dione) with Carbonyl Compounds

2,4-Dioxopentyltriphenylphosphonium bromide reacted with aqueous sodium hydrogencarbonate in dichloromethane to give, in almost quantitative yield, 1-(triphenylphosphoranylidene) pentane-2,4-dione. Dianion Wittig- and Michael Wittig condensations of the last mentioned phosphonium ylide with carbonyl compounds gave unsaturated 2,4-diketones which were almost totally enolised in deutero chloroform as 4-hydroxy-2-oxo-3,5-dienes (24–70% yields). These products closely resembled the type of compounds derived from similar condensations with alkyl 3-oxo-4-(triphenylphosphoranylidene)butanoate.     

Vibrational spectra of cyclopropenes. II. IR spectra of 1,2-disubstituted cyclopropenes

The IR spectra were measured and the vibrational problem was solved for the 1,2-dimethyl-3-phenylcyclopropene (I) and 1,2-diphenylcyclopropene (II) molecules. The forms of the normal vibrations were determined, and the vibrations associated with vibrations of the exo- and endocyclic bonds of the ring were distinguished. It was shown that substitution at the double bond of cyclopropene leads to a change in the form of the symmetrical vibration of the ring in comparison with the vibration of unsubstituted cyclopropene. It was shown that a significant hypsochromic shift of the band of the symmetrical ring vibration in 1,2-disubstituted cyclopropenes in comparison with cyclopropenes that do not contain substituents at the C^1,2 atoms is due chiefly to the kinematic effect of the substituent. It was found that the introduction of substituents at the double bond of the ring leads to a decrease in the force constant of the double bonds.St. Petersberg University. Translated from Zhurnal Strukturnoi Khimii, Vol. 34, No. 1, pp. 125–132, January–February, 1993.     

Synthesis and Reactivity Comparisons of 1‐Methyl‐3‐Substituted Cyclopropene Mini‐tags for Tetrazine Bioorthogonal Reactions

Substituted cyclopropenes have recently attracted attention as stable “mini‐tags” that are highly reactive dienophiles with the bioorthogonal tetrazine functional group. Despite this interest, the synthesis of stable cyclopropenes is not trivial and their reactivity patterns are poorly understood. Here, the synthesis and comparison of the reactivity of a series of 1‐methyl‐3‐substituted cyclopropenes with different functional handles is described. The rates at which the various substituted cyclopropenes undergo Diels–Alder cycloadditions with 1,2,4,5‐tetrazines were measured. Depending on the substituents, the rates of cycloadditions vary by over two orders of magnitude. The substituents also have a dramatic effect on aqueous stability. An outcome of these studies is the discovery of a novel 3‐amidomethyl substituted methylcyclopropene tag that reacts twice as fast as the fastest previously disclosed 1‐methyl‐3‐substituted cyclopropene while retaining excellent aqueous stability. Furthermore, this new cyclopropene is better suited for bioconjugation applications and this is demonstrated through using DNA templated tetrazine ligations. The effect of tetrazine structure on cyclopropene reaction rate was also studied. Surprisingly, 3‐amidomethyl substituted methylcyclopropene reacts faster than trans‐cyclooctenol with a sterically hindered and extremely stable tert‐butyl substituted tetrazine. Density functional theory calculations and the distortion/interaction analysis of activation energies provide insights into the origins of these reactivity differences and a guide to the development of future tetrazine coupling partners. The newly disclosed cyclopropenes have kinetic and stability advantages compared to previously reported dienophiles and will be highly useful for applications in organic synthesis, bioorthogonal reactions, and materials science.     

Alkyl Migration Aptitudes in the Vinylidene–Acetylene Rearrangement and Isotope Effect in the Vinylidene Formation Process from a Deuterium-Labeled Cyclopropene

The secret of the mechanism of vinylidene rearrangements has been unlocked by the use of specifically labeled cyclopropenes under mild thermal conditions (see the Equations). ¹³C labeling gives the surprising 1,2-alkyl migratory aptitude sequence Et>iPr>Me. Deuterium labeling yields the first measurement of the primary kinetic isotope effect in the ring opening of a cyclopropene to form a vinylidene.     

An unusually robust triple bond: synthesis, structure and reactivity of 3-alkynylcyclopropenes

Several 1,2-diphenyl- and 1,2,3-triphenyl-3-alkynylcyclopropenes have been prepared in moderate to very good yields by the reaction of acetylenic nucleophiles with the appropriate cyclopropenylium salt. Single crystal X-ray structures of four of the cyclopropenes were obtained. Stereoselective reduction of the triple bond failed in all cases, whereas model compounds lacking the cyclopropene moiety were reduced successfully. A rational for this lack of reactivity is proposed. The solution-phase thermochemistry of the 3-alkynyl-1,2,3-triphenylcyclopropenes was explored, affording 3-alkynyl-1H-indenes in moderate to good yields.     

Lipidated cyclopropenes via a stable 3-N spirocyclopropene scaffold

Lipidated cyclopropenes serve as useful bioorthogonal reagents for imaging cell membranes due to the cyclopropene’s small size and ability to ligate with pro-fluorescent tetrazines. Previously, the lipidation of cyclopropenes required modification at the C3 position because methods to append lipids at C1/C2 were not available. Herein, we describe C1/C2 lipidation with the biologically active lipid ceramide and a common phospholipid using a cyclopropene scaffold whose reactivity with 1,2,4,5-tetrazines has been caged.     

Computational studies on the mechanism of the gold(I)-catalysed rearrangement of cyclopropenes

Density functional theory calculations have been employed to investigate the mechanism of gold(I)-catalysed rearrangements of cyclopropenes. Product formation is controlled by the initial ring-opening step which results in the formation of a gold-stabilised carbocation/gold carbene intermediate. With 3-phenylcyclopropene-3-methylcarboxylate, the preferred intermediate allows cyclisation via nucleophilic attack of the carbonyl group and hence butenolide formation. Further calculations on simple model systems show that substituent effects can be rationalised by the charge distribution in the ring-opening transition state and, in particular, a loss of negative charge at what becomes the β-position of the intermediate. With 1-C(3)H(3)R cyclopropenes (R = Me, vinyl, Ph), ring-opening therefore places the substituent at the β-position.